Notch/Hes signaling and miR-9 engage in complex feedback interactions controlling neural progenitor cell proliferation and differentiation

Abstract

Canonical Notch signaling has diverse functions during nervous system development and is critical for neural progenitor self-renewal, timing of differentiation and specification of various cell fates. A key feature of Notch-mediated self-renewal is its fluctuating activity within the neural progenitor cell population and the oscillatory expression pattern of the Notch effector Hes1 and its target genes. A negative feedback loop between Hes1 and neurogenic microRNA miR-9 was found to be part of this oscillatory clock. In a recent study we discovered that miR-9 expression is further modulated by direct binding of the Notch intracellular domain/RBPj transcriptional complex to the miR-9_2 promoter. In turn, miR-9 not only targets Hes1 but also Notch2 to attenuate Notch signaling and promote neuronal differentiation. Here, we discuss how the two interwoven feedback loops may provide an additional fail-save mechanism to control proliferation and differentiation within the neural progenitor cell population. Furthermore, we explore potential implications of miR-9-mediated regulation of Notch/Hes1 signaling with regard to neural progenitor homeostasis, patterning, timing of differentiation and tumor formation.

A parametrized computational framework for description and design of genetic circuits of morphogenesis based on contact-dependent signaling and changes in cell-cell adhesion

“…Our results suggest that receptor expression can be used to generate stable intermediate states where sorting can be reverted. Interestingly, Notch receptor control via post-transcriptional mechanisms like microRNA have been shown to be used to stabilize different cell fates during choices of differentiation in human neuronal stem cells in particular in oscillating systems (Roese-Koerner et al, 2017).…”

H3.3 Barcoding of Nucleus Accumbens Transcriptional Activity Identifies Novel Molecular Cascades Associated with Cocaine Self-administration in Mice

“…Interestingly, the Sox family of transcription factors have also been associated with the regulation of opioid receptors and addiction (Im et al, 2001;Hwang et al, 2003Hwang et al, , 2004. The third transcription factor identified, Rbpj1, is a member of a family of molecules that are an integral part of Notch signaling, which regulates cell differentiation, cell fate, and neural progenitor selfrenewal (Roese-Koerner et al, 2017). Interestingly, Rbpj1 also regulates dopamine responsiveness in the striatum and may be a predictor of vulnerability to psychiatric disease (Toritsuka et al, 2017).…”

Prss56 expression in the rodent hypothalamus: Inverse correlation with pro‐opiomelanocortin suggests oscillatory gene expression in adult rat tanycytes

“…Such a model will also allow determination of the temporal dynamics of the putative oscillatory cycles. Interestingly, periodic oscillatory gene expression is common during development in mammalian stem cells and neural progenitor cells (Imayoshi & Kageyama, ; Roese‐Koerner, Stappert, & Brustle, ; Shimojo & Kageyama, ; Suzuki, Furusawa, & Kaneko, ; William et al, ), and tanycytes are now recognized as adult neural stem and progenitor cells because they can self‐renew and also differentiate into neurons or astrocytes (Chaker et al, ; Haan et al, ; Lee et al, ; Robins et al, ; Xu et al, ). Thus, periodic gene expression in tanycytes may be a characteristic related specifically to their stem/progenitor cell properties, which is also supported by the fact that Prss56 is specific to stem or progenitor cells in the brain, retina and skin (Gresset et al, ; Jourdon et al, ; Paylakhi et al, ).…”